Control of arthropods in animals

ABSTRACT

A method of controlling parasites in or on an animal comprising administering to the animal a parasiticidally effective, substantially non-emetic 1-arylpyrazole.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.09/727,684, filed Dec. 4, 2000, Now U.S. Pat. No. 6,569,886, whichclaims the benefit of U.S. Provisional Application No. 60/168,658, filedDec. 2, 1999, both of which are incorporated by reference herein intheir entireties and relied upon.

The present invention relates to a method of control of parasites inanimals, compositions comprising a compound effective for the saidcontrol and compounds effective against parasites.

It is generally a goal of agronomists and veterinarians to possesssufficient means to control pests, particularly arthropods, when theyattempt to invade or attack mammals, particularly domestic animalsand/or livestock. A classical method of controlling such pests has beenthe use of topical and/or systemic pesticides on or in the domesticanimal which is being attacked. Generally effective treatments includethe oral administration of insect growth regulators, such as lufenuron,or antihelminth compounds such as an ivermectin or an avermectin, or thetopical application of the insecticide fipronil. It is advantageous toapply pesticides to animals in oral form so as to prevent the possiblecontamination of humans or the surrounding environment.

It is an object of the present invention to provide new pesticides whichmay be used in domestic animals.

Another object of the invention is to provide safer pesticides fordomestic animals.

Another object of the invention is to provide new pesticides fordomestic animals that may be used in lower doses than existingpesticides.

These objects are met in whole or in part by the present invention.

U.S. Pat. No. 5,079,370, EP-A 0846686, WO 98/24769 and WO 97/28126disclose the use of arylpyrazoles as parasiticidal agents. However,these references are completely silent on the problem thatantiparasitical agents often elicit emesis in the animal to be protectedor cured from the parasites.

The present invention provides a method of controlling parasites in oron an animal comprising administering, preferably orally, to the animala parasiticidally effective, substantially non-emetic amount of a1-arylpyrazole of formula (I):

wherein:

-   R₂₀₁ is cyano, C(O)alkyl, C(S)NH₂, C(NH)OR₂₀₃, C(NH)SR₂₀₃, alkyl,    C(═NOH)NH₂, C(═NNH₂)NH₂, C(O)NH₂, C(O)NHR₂₀₅, C(O)NR₂₀₅R₂₀₆,    haloalkyl or heterocyclyl from the group:    optionally substituted by R₂₀₃;-   R₂₀₂ is S(O)_(h)R₂₀₃, C₂–C₆ alkenyl, C₂–C₆ haloalkenyl, cycloalkyl,    halocycloalkyl, cycloalkyl-alkyl, C₂–C₆ alkynyl, nitro or    imidazol-2-yl optionally substituted by alkyl, alkoxy, haloalkyl,    halogen, cyano and/or nitro;-   R₂₀₃ is alkyl or haloalkyl;-   R₂₀₄ is —OH, R₂₀₅O—, HC(O)O—, R₂₀₅C(O)O—, R₂₀₅OC(O)O—, NH₂C(O)O—,    R₂₀₅NHC(O)O—, R₂₀₅R₂₀₆NC(O)O—, R₂₀₅S(O)_(n)C(O)O—, R₂₀₆SO₂O—,    aryl-SO₂O—, (C₄–C₇)-oxacycloalkyloxy, R₂₀₅R₂₀₆N—C(NR₂₀₅)—O—,    R₂₀₅R₂₀₆N—C(NH)—O—, R₂₀₅NH—C(NR₂₀₅)—O—, R₂₀₅NH—C(NH)—O—,    R₂₀₅N═CH—O—, R₂₀₅N═C(R₂₀₆)—O—, R₂₀₅NH—C(S)—O—, R₂₀₅R₂₀₆N—C(S)—O—;-   R₂₀₅ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl,    haloalkoxyalkyl, adamantyl, aminoalkyl, alkylaminoalkyl,    dialkylaminoalkyl, haloalkylaminoalkyl, di(haloalkyl)aminoalkyl,    aryl optionally substituted, hetaryl optionally substituted,    arylalkyl optionally substituted, hetarylalkyl optionally    substituted, C₂–C₆ alkenyl, C₂–C₆ alkynyl;-   R₂₀₆ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl,    haloalkoxyalkyl, aryl optionally substituted, hetaryl optionally    substituted, arylalkyl optionally substituted, hetarylalkyl    optionally substituted;-   or R₂₀₅ and R₂₀₆ may form together with the nitrogen to which they    are attached a 3 to 7 membered ring which additionally may contain    one or more heteroatoms selected from nitrogen, oxygen and sulfur;-   X₁ is selected from nitrogen and C—R₂₁₂;-   R₂₁₁, R₂₁₂ are independently selected from halogen, hydrogen, CN,    C₁–C₃ alkyl and NO₂;-   R₂₁₃ is selected from halogen, haloalkyl, haloalkoxy, —S(O)_(k)CF₃,    and —SF₅ or forms a ring with R₂₁₄;-   R₂₁₄ is hydrogen or may constitute together with R₂₁₃ a group of    OCF₂O, CF₂OCF₂, CF₂OCF₂O and CF₂CF₂O, which forms together with the    carbons they are attached to a five to six membered ring; and-   h, k and n are independently selected from 0, 1, and 2;    and veterinarily acceptable salts thereof.

By the term “veterinarily acceptable salts” is meant salts the anions ofwhich are known and accepted in the art for the formation of salts forveterinary use. Suitable acid addition salts, e.g. formed by compoundsof formula (I) containing a basic nitrogen atom, e.g. an amino group,include salts with inorganic acids, for example hydrochlorides,sulphates, phosphates and nitrates and salts with organic acids forexample acetic acid.

When R₂₀₄ is OH the pyrazole structure can also be exhibited by itstautomeric form as pyrazolon structure.

Unless otherwise specified, alkyl and alkoxy groups are straight chainor branched and are generally lower alkyl and alkoxy groups, that ishaving from one to six carbon atoms, preferably from one to four carbonatoms. Generally, the haloalkyl, haloalkoxy and haloalkylamino groupshave from one to four carbon atoms. Halogen means F, Cl, Br, and I,preferably F and Cl. The haloalkyl and haloalkoxy and haloalkylaminogroups can bear one or more halogen atoms; preferred groups of this typeinclude —CF₃ and —OCF₃. Cycloalkyl groups generally have from 3 to 6carbon atoms, preferably from 3 to 5 carbon atoms and may be substitutedby one or more halogen atoms. Preferably in compounds of formula (I),alkyl groups are generally substituted by from one to five halogenatoms, preferably from one to three halogen atoms. Chlorine and fluorineatoms are preferred.

In compounds of formula (I) the following examples of radicals areprovided:

An example of cycloalkylalkyl is cyclopropylmethyl;

an example of cycloalkoxy is cyclopropyloxy; and

an example of alkoxyalkyl is CH₃OCH₂—.

Generally, in dialkylamino or di(haloalkyl)amino radicals, the alkyl andhaloalkyl groups on nitrogen may be chosen independently of one another.

Generally, the term “aryl” means a carbocyclic aromatic radical havingpreferably 6 to 14, in particular 6 to 12, carbon atoms, for examplephenyl, naphthyl or biphenylyl, preferably phenyl;

the term “heterocyclyl” preferably means a hetaryl or heteroaliphaticring system, “hetaryl” preferably being understood as meaning an arylradical in which at least one CH group is replaced by N and/or at leasttwo adjacent CH groups are replaced by S, NH or O, for example a radicalof thiophene, furan, pyrrole, thiazole, oxazole, imidazole, isothiazole,isoxazole, pyrazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole,1,3,4-triazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,4-triazole,1,2,3-triazole, 1,2,3,4-tetrazole, benzo[b]thiophene, benzo[b]furan,indole, benzo[c]thiophene, benzo[c]furan, isoindole, benzoxazole,benzothiazole, benzimidazole, benzisoxazole, benzisothiazole,benzopyrazole, benzothiadiazole, benzotriazole, dibenzofuran,dibenzothiophene, carbazole, pyridine, pyrazine, pyrimidine, pyridazine,1,3,5-triazine, 1,2,4-triazine, 1,2,4,5-triazine, quinoline,isoquinoline, quinoxaline, quinazoline, cinnoline, 1,8-naphthyridine,1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine, phthalazine,pyridopyrimidine, purine, pteridine or 4H-quinolizine;and the term “heteroaliphatic ring system” preferably means a(C₃–C₈)cycloalkyl radical in which at least one carbon unit is replacedby O, S or a group NR′ and R′ is hydrogen, (C₁–C₄)alkyl,(C₁–C₄)alkanoyl, (C₁–C₄)alkoxycarbonyl, (C₁–C₄)alkylsulfonyl,(C₁–C₄)alkoxy or aryl.

The substituents with which the various aliphatic, cycloaliphatic,aromatic and heterocyclic ring systems can be provided are, for example,halogen, nitro, cyano, di-(C₁–C₄)alkylamino, (C₁–C₄)alkyl,(C₃–C₈)cycloalkyl, (C₁–C₄)trialkylsilyl, (C₁–C₄)alkoxy,(C₁–C₄)alkoxy-(C₁–C₄)alkyl, (C₁–C₂)alkoxy-[CH₂CH₂O]_(0,1,2)-ethoxy,(C₁–C₄)alkylthio, (C₁–C₄)alkylsulfinyl, (C₁–C₄)alkylsulfonyl, phenyl,benzyl, phenoxy, halophenoxy, (C₁–C₄)alkylphenoxy, (C₁–C₄)alkoxyphenoxy,phenylthio, heterocyclyl, heterocyclylthio or heterocyclyloxy, it beingpossible for one or more, in the case of fluorine also up to the maximumnumber of, hydrogen atoms in the alkyl radicals and the radicals derivedtherefrom to be replaced by halogen, preferably chlorine or fluorine,where, in the event that these substituents are (C₁–C₄)alkyl, they mayalso be linked cyclically and where one or two aliphatic carbon units inthese fused ring systems, such as, for example, the indane, di-, tetra-or decahydronaphthyl or benzocycloheptane system, may be replaced byheteroatom units such as oxygen or sulfur and where one or more, in thecase of fluorine also up to the maximum number of, hydrogen atoms on thealiphatic carbon atom units can be replaced by halogen or (C₁–C₄)alkyl.

It is also to be understood that enantiomeric and diastereomeric formsof the compounds of formulae (I) and salts thereof are embraced by thepresent invention.

By the term non-emetic is meant a compound that does not generallyelicit emesis from the animal when a protective, preventative orcleaning dose is administered to the animal. By the term emesis is meantvomiting. Generally an emetic substance elicits the said emesis in lessthan 24 hours after administration, preferably less than 8 hours, morepreferably less than 2 hours. Generally when the compounds of theinvention are administered to a population of animals, more than 70% ofthe animals are free of emesis, preferably more than 80%, mostpreferably more than 90%.

Preferred compounds of the formula (I) are those wherein:

-   R₂₀₁ is cyano, C(O)alkyl, C(S)NH₂, alkyl, C(═NOH)NH₂ or C(═NNH₂)NH₂;-   R₂₀₂ is S(O)_(h)R₂₀₃, C₂–C₃ alkenyl, C₂–C₃ haloalkenyl, cycloalkyl,    halocycloalkyl, cycloalkyl-alkyl, C₂–C₃ alkynyl;-   R₂₀₃ is alkyl or haloalkyl;-   R₂₀₄ is —OH, R₂₀₅O—, HC(O)O—, R₂₀₅C(O)O—, R₂₀₅OC(O)O—, NH₂C(O)O—,    R₂₀₅NHC(O)O—, R₂₀₅R₂₀₆NC(O)O—, R₂₀₅S(O)_(n)C(O)O—;-   R₂₀₅ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl,    haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,    haloalkylaminoalkyl, di(haloalkyl)aminoalkyl,-   R₂₀₆ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl,    haloalkoxyalkyl, or R₂₀₅ and R₂₀₆ may form together with the    nitrogen to which they are attached a 3 to 7 membered ring which    additionally may contain one or more heteroatoms selected from    nitrogen, oxygen and sulfur;-   X₁ is selected from nitrogen and C—R₂₁₂;-   R₂₁₁, R₂₁₂ are independently selected from halogen, hydrogen, CN,    and NO₂;-   R₂₁₃ is selected from halogen, haloalkyl, haloalkoxy, —S(O)_(k)CF₃,    and —SF₅-   R₂₁₄ is hydrogen; and-   h, k and n are independently selected from 0, 1, and 2.

Further compounds of formula (I) which are preferred according to thepresent invention are those wherein:

-   R₂₀₁ is cyano;-   R₂₀₂ is S(O)_(h)R₂₀₃;-   R₂₀₃ is alkyl or haloalkyl;-   R₂₀₄ is OH or R₂₀₅O;-   X₁ is selected from nitrogen and C—R₂₁₂;-   R₂₁₁ and R₂₁₂ are independently selected from halogen, hydrogen, CN    and NO₂;-   R₂₁₃ is selected from halogen, haloalkyl, haloalkoxy, —S(O)_(k)CF₃,    and —SF₅; and-   h and k are independently selected from 0, 1, and 2.

The compounds of formula (I) of the present invention preferably haveone or more of the following features:

-   R₂₀₁ is cyano;-   R₂₀₃ is halomethyl, preferably CF₃;-   R₂₁₁ and R₂₁₂ are independently halogen;-   X₁ is C—R₂₁₂;-   R₂₁₃ is haloalkyl, haloalkoxy or —SF₅; or-   h is 0 or 1, or 2.

A further embodiment of the invention includes compounds of the formula(I), with the proviso that if R₂₀₁ is CN and R₂₀₂ is S(O)_(h)R₂₀₃ thenR₂₀₄ is not R₂₀₅O or R₂₀₅R₂₀₆N—C(O)—O—.

In another aspect of the present invention there is provided a method ofcontrolling parasites in or on an animal by administering to the animalan 1-arylpyrazole of formula (II):

wherein:

-   R₂₁ is cyano, C(═S)NH₂, C(═NOH)NH₂ or C(═NNH₂)NH₂;-   R₂₂ is S(O)_(m)R₂₃;-   R₂₃ is alkyl or haloalkyl;-   R₂₄ is OH, HC(O)O—, R₂₅C(O)O—, R₂₅OC(O)O—, R₂₅R₂₅—N—C(O)—O— or    R₂₅S(O)_(n)C(O)O—;-   R₂₅ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl,    haloalkoxyalkyl, adamantyl, adamantyl, aminoalkyl, alkylaminoalkyl,    dialkylaminoalkyl, haloalkylaminoalkyl, di(haloalkyl)aminoalkyl,    aryl optionally substituted, hetaryl optionally substituted,    arylalkyl optionally substituted, hetarylalkyl optionally    substituted, C₂–C₆ alkenyl, C₂–C₆ alkynyl;-   or two groups R₂₅ may form together with the nitrogen to which they    are attached a 3 to 7 membered ring which additionally may contain    one or more heteroatoms selected from nitrogen, oxygen and sulfur;-   X is selected from nitrogen and C—R₃₂;-   R₃₁ and R₃₂ are independently selected from halogen, hydrogen, CN,    C₁–C₃ alkyl and NO₂;-   R₃₃ is selected from halogen, haloalkyl, haloalkoxy, —S(O)_(r)CF₃,    and —SF₅ or forms a ring together with R₃₄;-   R₃₄ is hydrogen or may constitute together with R₂₁₃ a group of    OCF₂O, CF₂OCF₂, CF₂OCF₂O and CF₂CF₂O, which forms together with the    carbons they are attached to a five to six membered ring;-   m is 0, 1 or 2;-   r is selected from 0, 1, and 2;    and veterinarily acceptable salts thereof;    provided that if R₂₁ is cyano then R₂₄ is not R₂₅R₂₅—N—C(O)—O—.

Preferred are compounds of formula (II),

wherein:

-   R₂₁ is cyano, C(═S)NH₂, C(═NOH)NH₂ or C(═NNH₂)NH₂;-   R₂₂ is S(O)_(m)R₂₃;-   R₂₃ is alkyl or haloalkyl;-   R₂₄ is OH, HC(O)O—, R₂₅C(O)O—, R₂₅OC(O)O— or R₂₅S(O)_(n)C(O)O—;-   R₂₅ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl,    haloalkoxyalkyl;-   X is selected from nitrogen and C—R₃₂;-   R₃₁ and R₃₂ are independently selected from halogen, hydrogen, CN,    C₁–C₃ alkyl and NO₂;-   R₃₃ is selected from halogen, haloalkyl, haloalkoxy, —S(O)_(r)CF₃,    and —SF₅.

In another aspect of the present invention there is provided a compoundof formula (II) or salt thereof as hereinbefore described with theproviso that the compound is not1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-5-hydroxypyrazole.

A further preferred class of compounds of formula (II) are thosewherein:

-   R₂₁ is cyano;-   R₂₂ is S(O)_(m)R₂₃;-   R₂₃ is haloalkyl, preferably CF₃;-   R₂₄ is OH;-   X is selected from nitrogen and C—R₃₂;-   R₃₁ and R₃₂ are independently selected from halogen,-   R₃₃ is selected from halogen, haloalkyl, haloalkoxy, —S(O)_(r)CF₃,    and —SF₅;-   m and r are independently selected from 0, 1, and 2    with the proviso that the compound is not    1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-5-hydroxypyrazole.

In a further aspect of the invention the following groups of compoundsare provided:

Compounds of the formula (I), wherein

-   R₂₀₁ is C(O)NH₂, C(O)NHR₂₀₅, C(O)NR₂₀₅R₂₀₆, C(O)N═S(R₂₀₃)₂,    haloalkyl or heterocyclyl from the group:    optionally substituted by R₂₀₃;

Compounds of the formula (I), wherein

-   R₂₀₂ is nitro or imidazol-2-yl optionally substituted by alkyl,    alkoxy, haloalkyl, halogen, cyano, nitro;

Compounds of the formula (I), wherein

-   R₂₀₄ is R₂₀₆SO₂O—, aryl-SO₂O—, (C₄–C₇)-oxacycloalkyloxy,    R₂₀₅R₂₀₆N—C(NR₂₀₅)—O—, R₂₀₅R₂₀₆N—C(NH)—O—, R₂₀₅NH—C(NR₂₀₅)—O—,    R₂₀₅NH—C(NH)—O—, R₂₀₅N═CH—O—, R₂₀₅N═C(R₂₀₆)—O—, R₂₀₅NH—C(S)—O—,    R₂₀₅R₂₀₆N—C(S)—O—;

Compounds of the formula (I), wherein

-   R₂₁₄ constitute together with R₂₁₃ a group of OCF₂O, CF₂OCF₂,    CF₂OCF₂O and CF₂CF₂O, which forms together with the carbons they are    attached to a five to six membered ring.

The compounds1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluromethylsulfinyl-5-hydroxypyrazoleand1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluromethylsulfonyl-5-hydroxypyrazoleare highly preferred compounds according to the invention.

The following compounds of formula (I) are preferred according to thepresent invention as listed in Tables 1 to 3. The Compound Numbers arefor identification purposes only. The following symbols are herebydefined: Me means methyl; Et means ethyl; n-Pr means n-propyl; i-Prmeans isopropyl; n-Bu means n-Butyl; and Ph means Phenyl.

TABLE 1 Compounds of formula (I) wherein R₂₀₁ is cyano; R₂₀₂ is SCF₃;R₂₁₁ is Cl, X₁ is C—Cl, R₂₁₄ is H and R₂₁₃ is CF₃ or SF₅. Phys. data:melting point (° C.) or NMR (¹H, ¹⁹F-NMR, ppm) Compound Compound NumberNumber (R₂₁₃ = CF₃) (R₂₁₃ = SF₅) R₂₀₄ Phys. data  1-1  1-2 OH 19F: −44.9−63.8  2-1  2-2 OMe mp. 83  3-1  3-2 OEt mp. 105  4-1  4-2 OPr  5-1  5-2O-i-Pr  6-1  6-2 O-n-Bu  7-1  7-2 OCH₂OMe  8-1  8-2 OCH₂CH₂OMe  9-1  9-2OCH₂OEt 10-1 10-2 OCH₂CH₂OEt 11-1 11-2 OC(O)Me 12-1 12-2 OC(O)Et 13-113-2 OC(O)n-Pr 14-1 14-2 OC(O)H 15-1 15-2 OC(O)NH₂ 16-1 16-2 OC(O)NHMe17-1 17-2 OC(O)NHEt 18-1 18-2 OC(O)NHnPr 19-1 19-2 OC(O)NMe₂ mp. 126

TABLE 2 Compounds of formula (I) wherein R₂₀₁ is cyano; R₂₀₂ is SOCF₃;R₂₁₁ is Cl, X₁ is C—Cl, R₂₁₄ is H and R₂₁₃ is CF₃ or SF₅. Phys. data:melting point (° C.) or NMR (¹H, ¹⁹F-NMR, ppm) Compound Compound NumberNumber (R₂₁₃ = CF₃) (R₂₁₃ = SF₅) R₂₀₄ Phys. data  1-3  1-4 OH mp. 185 2-3  2-4 OMe mp. 136  3-3  3-4 OEt mp. 157  4-3  4-4 OPr  5-3  5-4O-i-Pr  6-3  6-4 O-n-Bu  7-3  7-4 OCH₂OMe  8-3  8-4 OCH₂CH₂OMe  9-3  9-4OCH₂OEt 10-3 10-4 OCH₂CH₂OEt 11-3 11-4 ONa 19F: −60.9 −72.6 12-3 12-4OC(O)Et 13-3 13-4 OC(O)n-Pr 14-3 14-4 OC(O)H 15-3 15-4 OC(O)NH₂ 16-316-4 OC(O)NHMe 17-3 17-4 OC(O)NHEt 18-3 18-4 OC(O)NHnPr 19-3 19-4OC(O)NMe₂

TABLE 3 Compounds of formula (I) wherein R₂₀₁ is cyano; R₂₀₂ is SO₂CF₃;R₂₁₁ is Cl, X₁ is C—Cl, R₂₁₄ is H and R₂₁₃ is CF₃ or SF₅. Phys. data:melting point (° C.) or NMR (¹H, ¹⁹F-NMR, ppm) Compound Compound NumberNumber (R₂₁₃ = CF₃) (R₂₁₃ = SF₅) R₂₀₄ Phys. data  1-5  1-6 OH 19F: −63.8−79.9  2-5  2-6 OMe mp. 151  3-5  3-6 OEt mp. 132  4-5  4-6 OPr  5-5 5-6 O-i-Pr  6-5  6-6 O-n-Bu  7-5  7-6 OCH₂OMe  8-5  8-6 OCH₂CH₂OMe  9-5 9-6 OCH₂OEt 10-5 10-6 OCH₂CH₂OEt 11-5 11-6 OC(O)Me 12-5 12-6 OC(O)Et13-5 13-6 OC(O)n-Pr 14-5 14-6 OC(O)H 15-5 15-6 OC(O)NH₂ 16-5 16-6OC(O)NHMe 17-5 17-6 OC(O)NHEt 18-5 18-6 OC(O)NHnPr 19-5 19-6 OC(O)NMe₂

TABLE 4 Compounds of formula (I) wherein R₂₀₁ is alkyl or haloalkyl;R₂₀₂ is SO_(h)R₂₀₃; R₂₁₁ is Cl, X₁ is C—Cl, R₂₁₄ is H and R₂₁₃ is CF₃;Phys. data: melting point (° C.) or NMR (¹H, ¹⁹F-NMR, ppm) Compound NoR₂₀₁ R₂₀₂ R₂₀₄ Phys. Data  1-7 CH₃ SCF₃ OH 19F: −45.9 −63.5  2-7 CH₃SOCF₃ OH  3-7 CH₃ SO₂CF₃ OH  4-7 CH₃ SCClF₂ OH 19F: −30.4 −63.7  5-7 CH₃SOCClF₂ OH  6-7 CH₃ SO₂CClF₂ OH  7-7 CH₃ SCCl₂F OH  8-7 CH₃ SOCCl₂F OH 9-7 CH₃ SC₂F₅ OH 10-7 CH₃ SC₂H₅ OH 11-7 CH₃ SCF₃ OMe 12-7 CH₃ SCF₃ OEt13-7 CH₃ SMe OH 14-7 C₂H₅ SCF₃ OH 15-7 CF₃ SCF₃ OH 16-7 CHF₂ SCF₃ OH17-7 CF₃ SOCF₃ OH 18-7 CF₃ SO₂CF₃ OH 19-7 CF₃ SCClF₂ OH 20-7 CF₃ SCCl₂FOH

TABLE 5 Compounds of formula (I) wherein R₂₀₂ is SO_(h)R₂₀₃; R₂₁₁ is Cl,X₁ is C—Cl, R₂₁₄ is H and R₂₁₃ is CF₃; Phys. data: melting point (° C.)or NMR (¹H, ¹⁹F-NMR, ppm) Compound No R₂₀₁ R₂₀₂ R₂₀₄ Phys. data  1-8CONH₂ SCF₃ OH mp. 197  2-8 CONH₂ SOCF₃ OH  3-8 CONH₂ SO₂CF₃ OH  4-8CSNH₂ SCF₃ OH mp. 150  5-8 CSNH₂ SOCF₃ OH  6-8 CSNH₂ SO₂CF₃ OH  7-8CONMe₂ SCF₃ OH  8-8 C(NOH)NH₂ SCClF₂ OH mp. 156  9-8 C(NOH)NH₂ SCF₃ OHmp. 184 10-8 COCH₃ SCF₃ OH 19F: −44.5 −61.7 11-8 COCH₃ SCClF₂ OH 19F:−29.4 −61.0 12-8 CONH₂ SCF₃ OEt 13-8 CONH₂ SCClF₂ OEt 14-8Oxadiazolin-3-yl SCF₃ OH 15-8 Oxazolin-2-yl SCF₃ OH 16-8 CON═S(iPr₂)SCF₃ OH 17-8 CON═S(iPr)₂ SOCF₃ OH 18-8 CON═S(iPr)₂ SO2CF₃ OH 19-8 CONH₂SCF₃ OMe mp. 148–151

TABLE 6 Compounds of formula (I) wherein R₂₀₁ is CN; R₂₀₂ is SO_(h)R₂₀₃;R₂₁₁ is Cl, X₁ is C—Cl, R₂₁₄ is H and R₂₁₃ is CF₃; Phys. data: meltingpoint (° C.) or NMR (¹H, ¹⁹F-NMR, ppm) Com- pound No R₂₀₂ R₂₀₄ Phys.data  1-9 SCClF₂ OH 19F: −30.7 −63.7  2-9 SOCClF₂ OH  3-9 SO₂CClF₂ OH 4-9 SCCl₂F OH  5-9 SOCCl₂F OH  6-9 SO₂CCl₂F OH  7-9 SC₂F₅ OH  8-9SCH₂CF₃ OH  9-9 SCCl₂CF₃ OH 10-9 SCCl₂CH₃ OH 11-9 SC₂H₅ OH 1H: 1.25, 3H;2.71, 3H; 7.72, 2H; 12-9 SCHF₂ OH 13-9 SCClF₂ OEt mp. 91 14-9 SOCClF₂OEt mp. 161 15-9 SCClF₂ OCONMe₂ 16-9 SCClF₂ OCOtBu 17-9 SCH₃ OH mp. 6618-9 SCH₃ OCONMe₂ 1H: 2.43, 3H; 2.96, 6H; 7.75, 2H; 19-9 SCBrF₂ OH 20-9SCCl₃ OH 21-9 SCCl₂F OMe mp. 154 22-9 SOCCl₂F OMe mp. 136 23-9 SO₂CCl₂FOMe mp. 189 24-9 SO₂CClF₂ OEt mp. 130 25-9 SCClF₂ OMe mp. 87 26-9SOCClF₂ OMe mp. 139 27-9 SO₂CClF₂ OMe mp. 166

TABLE 7 Compounds of formula (I) wherein R₂₀₁ is CN; R₂₀₂ is SO_(h)R₂₀₃;R₂₁₁ is Cl, X₁ is C—Cl, R₂₁₄ is H and R₂₁₃ is CF₃; Phys. data: meltingpoint (° C.) or NMR (¹H, ¹⁹F-NMR, ppm) Compound No R₂₀₂ R₂₀₄ Phys. data 1-10 SCF₃ OCH₂—CCH 19F: −44.6 −63.8  2-10 SCF₃ OCH₂COOEt mp. 71  3-10SCF₃ OCOtBu mp. 82  4-10 SCF₃ OCO—Ph-4-OMe 19F: −43.5 −63.9  5-10 SCF₃OSO₂Me mp. 110  6-10 SCF₃ OCO-Pyrrolidin mp. 101  7-10 SCF₃OCO-Morpholin 19F: −43.5 −63.8  8-10 SCF₃ OCO—N(i-Pr)₂ mp. 120  9-10SCF₃ OCO-NPh₂ mp. 142 10-10 SCF₃ OCO-N(Me)Ph 19F: −43.6 −63.7 11-10 SCF₃OCO-Carbazol mp. 148 12-10 SCF₃ OCO-Adamantyl mp. 142 13-10 SCF₃OCO-Mesityl mp. 103 14-10 SCF₃ OCH₂Ph mp. 73 15-10 SCF₃ OSO₂-4-Tolyl16-10 SCF₃ O—C(NMe)NMe₂ 17-10 SCF₃ O—CH═NC₂H₄OEt 18-10 SCF₃ OCH₂CONH₂mp. 156 19-10 SCF₃ O—C(N(i-Pr))NHiPr 20-10 SCF₃ O—C(S)-NHEt

TABLE 8 Compounds of formula (I) wherein R₂₁₁ is Cl, X₁ is C—Cl, R₂₁₄ isH and R₂₁₃ is CF₃; Phys. data: melting point (° C.) or NMR (¹H, ¹⁹F-NMR,ppm) Compound No R₂₀₁ R₂₀₂ R₂₀₄ Phys. data  1-11 CN4,5-Dicyanoimidazol-2-yl OH  2-11 CN 4,5-Dicyanoimidazol-2-yl OEt  3-11CH₃ 4,5-Dicyanoimidazol-2-yl OH  4-11 CH₃ 4,5-Dicyanoimidazol-2-yl OEt1H: 1.28, 3H; 2.55, 3H; 4.08, 2H; 7.77, 2H;  5-11 CN —CH═CCl₂ OEt  6-11CN —CH₂CH=CH₂ OAllyl mp. 62–66  7-11 CN —CH═CBr₂ OEt  8-11 CNCyclopropyl OEt  9-11 CN c-C₆H₁₁ OEt 10-11 CN NO₂ OH mp. 107 11-11 CNNO₂ OEt 12-11 CN —CC—Me OEt 13-11 CN —CC—SiMe₃ OEt

TABLE 9 Compounds of formula (I) wherein R₂₀₁ is CN; R₂₀₂ is SO_(h)R₂₀₃;R₂₁₁ is Cl, R₂₁₄ and R₂₁₃ form the unit CF₂OCF₂; Phys. data: meltingpoint (° C.) or NMR (¹H, ¹⁹F-NMR, ppm) Compound No R₂₀₂ R₂₀₄ X = CR₂₁₂Phys. data  1-12 SCF₃ OH CH  2-12 SCF₃ OH C—Cl  3-12 SCF₃ OEt C—Cl  4-12SOCF₃ OH CH  5-12 SOCF₃ OH C—Cl  6-12 SO₂CF₃ OH CH  7-12 SO₂CF₃ OH C—Cl 8-12 SCClF₂ OH C—Cl  9-12 SCCl₂F OH C—Cl 10-12 SC₂H₅ OH C—Cl

TABLE 10 Compounds of formula (I) wherein R₂₀₁ is CN; R₂₀₂ isSO_(h)R₂₀₃; R₂₁₁ is Cl, X₁ is C—Cl, R₂₁₄ is H and R₂₁₃ is OCF₃; Phys.data: melting point (° C.) or NMR (¹H, ¹⁹F-NMR, ppm) Compound No R₂₀₂R₂₀₄ Phys data  1-13 SCF₃ OH  2-13 SOCF₃ OH  3-13 SO₂CF₃ OH  4-13 SCF₃OMe mp. 101  5-13 SOCF₃ OMe mp. 104  6-13 SO₂CF₃ OMe mp. 117  7-13SCCl₂F OMe mp. 123  8-13 SCF₃ OEt  9-13 SOCF₃ OEt 10-13 SO₂CF₃ OEt

METHODS OF SYNTHESIS Method 1

The compounds of formula (I) and (II) with R₂₀₄/R₂₄=OH and R₂₂=SR₂₃ canbe synthesized by reacting 5-hydroxypyrazoles with sulfenylchlorideswith or without bases in organic solvents (see e.g. EP-A-295 117):

The compounds of formula (I) and (II) with R₂₀₄/R₂₄=OH and R₂₂=SR₂₃ canbe synthesized by reacting 5-hydroxypyrazoles with disulfur dichloride.The resulting pyrazoledisulfides can be alkylated to yield4-pyrazolsulfides (see e.g., EP-A-374 061, EP295117, C. Wakselman, J.Chem. Soc. Perkin Trans 1, 1992, 3371–3375):

The compounds of formula (I) and (II) with R₂₀₄/R₂₄=OH andR₂₂=S(O)_(a)R₂₃ (a=1,2) can be synthesized by reacting pyrazolsulfidesR₂₂=SR₂₃ with oxidizing agents like peroxy compounds (hydrogen peroxide,organic peroxides as peroxyacetic acid), halogen derivatives (likeperiodate salts) and others to obtain sulfoxides R₂₂=SOR₂₃ and sulfonesR₂₂=SO₂R₂₃ (see e.g. EP-A-295 117).

In another aspect of the present invention, compounds of formula (II)wherein R₂₄ is HC(O)O—, R₂₅C(O)O—, R₂₅OC(O)O—, or R₂₅S(O)_(n)C(O)O andR₂₁, R₂₂, R₃₁, R₃₃, X and n are defined above are generally prepared byreaction of compounds of formula (II) wherein R₂₄ is OH and R₂₁, R₂₂,R₃₁, R₃₃, X and n are defined above with compounds of formulae (III),(IV), (V), and (VI) respectively wherein X₂ is a leaving group such as ahalogen atom or an acetyl group:HC(O)X₂  (III)R₂₅C(O)X₂  (IV)R₂₅OC(O)X₂  (V)R₂₅S(O)_(n)C(O)X₂  (VI)

Compounds of general formula (II) wherein R₂₄ is OH and R₂₁, R₂₂, R₃₁,R₃₃, X and n are defined above may be prepared by methods known in theart generally or by methods described in International PatentPublications WO 94/21606, WO 97/07102, WO 98/24767, WO 98/28277, WO98/28278 and WO 98/28279, European Patent Application 385809, and U.S.Pat. No. 5,232,940, 5,047,550 or other methods known to the personskilled in the art.

The present invention also relates to a composition comprising aparasiticidally effective, substantially non-emetic amount of a compoundof formula (I) or a salt thereof and an acceptable carrier. Acceptablecarriers for the use of the compounds are generally known to the skilledaddressee concerned with pest control in animals, particularly domesticanimals, most preferably dogs or cats.

The compositions which can be used in the invention can comprisegenerally from about 0.001 to 95% of the compound of formula (I) or asalt thereof. The remainder of the composition up to 100% comprises acarrier as well as generally various additives. In this specificationand the accompanying claims, percentages are by weight.

The diluted liquid formulations generally comprise from about 0.001 toabout 3% of compound of formula (I) or a salt thereof, preferably fromabout 0.1 to about 0.5%.

Solid formulations generally comprise from about 0.1 to about 8% ofcompound of formula (I) or a salt thereof, preferably from about 0.5 toabout 1.5%.

Compositions for oral administration comprise one or more of thecompounds of general formula (I) or salts thereof in association withveterinarily acceptable carriers or coatings and include, for example,tablets, pills, capsules, gels, drenches, medicated feeds, medicateddrinking water, medicated dietary supplements, slow-release boluses orother slow-release devices intended to be retained within thegastro-intestinal tract. Any of these may incorporate the activeingredients contained within micro-capsules or coated with acid-labileor alkali-labile or other pharmaceutically acceptable enteric coatings.Feed premixes or concentrates containing compounds of the presentinvention for use in preparation of medicated diets, drinking water orother materials for consumption by animals may also be used. In a highlypreferred embodiment, the compositions are administered postprandially,preferably from just after a meal to 2 hours after the meal.

In a highly preferred embodiment, there is provided a product which isreadily chewed by the animal and which product does generally not allowhuman contamination when the product is provided to the animal by hand.

The compounds of general formula (I) or salts thereof may beadministered before, during or after meals. The compounds of generalformula (I) or salts thereof may be mixed with a carrier and/or afoodstuff.

According to the present invention the compound of formula (I) or a saltthereof is administered orally in a dose to the animal in a dose rangegenerally from 0.1 to 500 mg/kg of the compound of formula (I) or a saltthereof per kilogram of animal body weight (mg/kg), preferably from 1 to100 mg/kg, more preferably from 1 to 50 mg/kg, even more preferably from2 to 25 mg/kg, most preferably from 3 to 15 mg/kg.

According to the present invention, the frequency of treatment of theanimal, preferably the domestic animal to be treated by the compound offormula (I) or a salt thereof is generally from about once per week toabout once per year, preferably from about once every two weeks to aboutonce every six months, more preferably from about once every two weeksto once every three months, and most preferably from about once everytwo weeks to about once every six weeks.

Generally the animal to be treated is a domestic animal, preferably adomestic companion animal. More preferably the animal to be treated is adog and/or a cat.

Accordingly, in a preferred embodiment there is provided a method ofcontrolling parasites in or on a cat comprising administering orally tothe cat a parasitically effective, substantially non emetic amount of a1-arylpyrazole of formula (I).

In a further preferred embodiment there is provided a method ofcontrolling parasites in or on a dog comprising administering orally tothe dog a parasitically effective, substantially non emetic amount of a1-arylpyrazole of formula (I).

The present invention also relates to a composition comprising aparasiticidally effective amount of a compound of formula (II) or a saltthereof and an acceptable carrier. Acceptable carriers for the use ofthe compounds are generally known to the skilled addressee concernedwith pest control in animals, particularly domestic animals, mostpreferably dogs or cats.

In another aspect of the present invention, the compounds of formula(II) or salts thereof may be used in the field of veterinary medicine orlivestock husbandry or in the maintenance of public health againstarthropods, helminths or protozoa which are parasitic internally orexternally upon vertebrates, particularly warm-blooded vertebrates, forexample domestic animals, e.g., cattle, sheep, goats, equines, swine,poultry, dogs or cats.

The compounds are administered to animals infested by or exposed toinfestation by arthropods, helminths or protozoa, by parenteral, oral ortopical application of compositions in which the active ingredientexhibits an immediate and/or prolonged action over a period of timeagainst the arthropods, helminths or protozoa, for example byincorporation in feed or suitable orally-ingestible pharmaceuticalformulations, edible baits, salt licks, dietary supplements, pour-onformulations, sprays, baths, dips, showers, jets, dusts, greases,shampoos, creams, wax smears or livestock self-treatment systems.

Solid or liquid compositions for application topically to animals,timber, stored products or household goods usually contain from about0.00005% to about 90%, more particularly from about 0.001% to about 10%,by weight of one or more compounds of formula (II) or veterinarilyacceptable salts thereof. For administration to animals orally orparenterally, including percutaneously, in solid or liquid compositions,these normally contain from about 0.1% to about 90% by weight of one ormore compounds of formula (II) or veterinarily acceptable salts thereof.Medicated feedstuffs normally contain from about 0.001% to about 3% byweight of one or more compounds of formula (II) or veterinarilyacceptable salts thereof. Concentrates or supplements for mixing withfeedstuffs normally contain from about 5% to about 90%, preferably fromabout 5% to about 50%, by weight of one or more compounds of formula(II) or veterinarily acceptable salts thereof. Mineral salt licksnormally contain from about 0.1% to about 10% by weight of one or morecompounds of formula (II) or veterinarily acceptable salts thereof.

Dusts or liquid compositions for application to livestock, goods,premises or outdoor areas may contain from about 0.0001% to about 15%,more especially from about 0.005% to about 2.0%, by weight, of one ormore compounds of formula (II) or veterinarily acceptable salts thereof.Suitable concentrations in treated waters are between about 0.0001 ppmand about 20 ppm, more particularly about 0.001 ppm to about 5.0 ppm. ofone or more compounds of formula (II), or veterinarily acceptable saltsthereof, and may be used therapeutically in fish farming withappropriate exposure times. Edible baits may contain from about 0.01% toabout 5%, preferably from about 0.01% to about 1.0%, by weight, of oneor more compounds of formula (II) or veterinarily acceptable saltsthereof.

When administered to vertebrates parenterally, orally or by percutaneousor other means, the dosage of compounds of formula (II), or veterinarilyacceptable salts thereof, will depend upon the species, age, or healthof the vertebrate and upon the nature and degree of its actual orpotential infestation by arthropod, helminth or protozoan pests. Asingle dose of about 0.1 to about 500, preferably from 0.1 to about 100mg, preferably about 2.0 to about 20.0 mg, per kg body weight of theanimal or doses of about 0.01 to about 20.0 mg, preferably about 0.1 toabout 5.0 mg, per kg body weight of the animal per day, for sustainedmedication, are generally suitable by oral or parenteral administration.By use of sustained release formulations or devices, the daily dosesrequired over a period of months may be combined and administered toanimals on a single occasion.

The compounds of the invention may be administered most advantageouslywith another parasiticidally effective material, such as anendoparasiticide, and/or an ectoparasiticide, and/or anendectoparasiticide. For example, such compounds include macrocycliclactones such as avermectins or milbemycins e.g., ivermectin; pyratel(generally adminsitered as pyrantel pamoate) or an insect growthregulator such as lufenuron or methoprene.

By the term “parasites” as used in the specification and claims is meantendoparasites and ectoparasites of warm-blooded animals, particularlyectoparasites. Preferably, fleas and/or ticks are controlled by themethod of the present invention.

Illustrative of specific parasites of various host animals which may becontrolled by the methods of this invention include arthropods such as:

Mites: Mesostigmata spp. e.g., mesostigmatids such as the chicken mite,Dermanyssus gallinae; itch or scab mites such as Sarcoptidae spp. forexample Sarcoptes scabiei; mange mites such as Psoroptidae spp.including Chorioptes bovis and Psoroptes ovis; chiggers e.g.,Trombiculidae spp. for example the north american chigger, Trombiculaalfreddugesi;

Ticks: e.g., soft-bodied ticks including Argasidae spp. for exampleArgas spp. and Ornithodoros spp; hard-bodied ticks including Ixodidaespp., for example Rhipicephalus sanguineus, and Boophilus spp.;

Lice: sucking lice, e.g., Menopon spp. and Bovicola spp.; biting lice,e.g., Haematopinus spp., Linognathus spp. and Solenopotes spp.;

Fleas: e.g., Ctenocephalides spp., such as dog flea (Ctenocephalidescanis) and cat flea (Ctenocephalides felis); Xenopsylla spp. such asoriental rat flea [Xenopsylla cheopis]; and Pulex spp. such as humanflea [Pulex irritans];

True bugs: e.g., Cimicidae or including the common bed bug (Cimexlectularius);, Triatominae spp. including triatomid bugs also known askissing bugs; for example Rhodnius prolixus and Triatoma spp.;

bloodsucking adult flies: (e.g., horn fly [Haematobia irritans], horsefly [Tabanus spp.], stable fly [Stomoxys calcitrans], black fly[Simulium spp.], deer fly [Chrysops spp.], louse fly [Melophagusovinus], tsetse fly [Glossina spp.], mosquitoes [Culex spp., Anophelesspp., and Aedes spp.); and

parasitic fly maggots: (e.g., bot fly [Oestrus ovis and Cuterebra spp.],blow fly [Phaenicia spp.], screwworm [Cochliomyia hominivorax], cattlegrub [Hypoderma spp.], fleeceworm.

The present invention also provides for the use of a compound of formula(I) or a salt thereof hereinbefore described as a therapeutic agent,preferably for animals, more preferably for domestic animals.

The veterinary composition may be sterile or non-sterile. It may be aliquid (e.g., aqueous) or solid (e.g., dry) composition, in particular afreeze-dried composition, from which, by addition of water or anotherliquid, orally effective solutions may be prepared.

The present invention also provides for the use of a compound of formula(I) or a salt thereof as hereinbefore defined for the manufacture of aveterinary composition for the control of parasites in or on an animal.

In a further embodiment of the invention there is provided the use of acompound of formula (I) or salt thereof for controlling parasites in oron an animal without causing emesis of the animal.

Preferred is the use for orally administering the compound to theanimal, which is preferably a domestic animal, highly preferred a cat ora dog.

In a further embodiment of the invention there is provided the use of acompound of formula (I) or salt thereof for the manufacture of asubstantially non-emetic composition, for controlling parasites in or onan animal, preferably for oral administering.

The present invention also relates to a method of cleaning animals ingood health comprising the application to the animal of a compound offormula (I) or a salt thereof as hereinbefore defined to the animal.

The method of cleaning an animal is not a method of treatment by therapyof the animal body per se, because

(a) the animal is in good health and requires no substantial treatmentto correct a deficiency of health;

(b) the cleaning of the animal is not intended to be done by veterinarypersonnel, but by persons interested in the cleaning of the animal; and

(c) the purpose of such cleaning is to avoid unpleasant conditions forhumans and the environment in which humans inhabit so as to not infestthe said humans with arthropods carried by the animal.

By “carrier” is meant an organic or inorganic material, which can benatural or synthetic, and which is associated with the compound andwhich facilitates its application to the animal. This carrier is thusgenerally inert and should be arthropodicidally acceptable. The carriercan be solid (e.g., clay, silicates, silica, resins, wax) or liquid(e.g., water, alcohols, ketones, oil solvents, polar aprotic solvents).An example of an oil solvent is corn oil. An example of a polar aproticsolvent is dimethyl sulfoxide.

The compounds of the invention also have utility in the control ofarthropod or nematode pests of plants. The active compound is generallyapplied to the locus in which arthropod or nematode infestation is to becontrolled at a rate of about 0.005 kg to about 25 kg of active compoundper hectare of locus treated, preferably 0.02 to 2 kg/ha. Under idealconditions, depending on the pest to be controlled, the lower rate mayoffer adequate protection. On the other hand, adverse weatherconditions, resistance of the pest and other factors may require thatthe active ingredient be used in higher proportions. For foliarapplication, a rate of 0.01 to 1 kg/ha may be used.

When the pest is soil-borne, the formulation containing the activecompound is distributed evenly over the area to be treated in anyconvenient manner. Application may be made, if desired, to the field orcrop-growing area generally or in close proximity to the seed or plantto be protected from attack. The active component can be washed into thesoil by spraying with water over the area or can be left to the naturalaction of rainfall. During or after application, the formulation can, ifdesired, be distributed mechanically in the soil, for example byploughing or disking. Application can be prior to planting, at planting,after planting but before sprouting has taken place or after sprouting.

The compounds of the invention may be applied in solid or liquidcompositions to the soil principally to control those nematodes dwellingtherein but also to the foliage principally to control those nematodesattacking the aerial parts of the plants (e.g., aphelenchoides spp. andditylenchus spp. listed above).

The compounds of the invention are of value in controlling pests whichfeed on parts of the plant remote from the point of application, e.g.,leaf feeding insects are killed by the subject compounds applied toroots. In addition the compounds may reduce attacks on the plant bymeans of antifeeding or repellent effects.

The compounds of the invention are of particular value in the protectionof field, forage, plantation, glasshouse, orchard and vineyard crops, orornamentals and of plantation and forest trees, for example, cereals(such as maize, wheat, rice, sorghum), cotton, tobacco, vegetables andsalads (such as beans, cole crops, curcurbits, lettuce, onions, tomatoesand peppers), field crops (such as potato, sugar beet, ground nuts,soyabean, oil seed rape), sugar cane, grassland and forage (such asmaize, sorghum, lucerne), plantations (such as of tea, coffee, cocoa,banana, oil palm, coconut, rubber, spices), orchards and groves (such asof stone and pip fruit, citrus, kiwifruit, avocado, mango, olives, andwalnuts), vineyards, ornamental plants, flowers and shrubs under glassand in gardens and parks, forest trees (both deciduous and evergreen) inforests, plantations and nurseries.

They are also valuable in the protection of timber (standing, felled,converted, stored or structural) from attack by sawflies (e.g.,urocerus) or beetles (e.g., scolytids, platypodids, lyctids,bostrychids, cerambycids, anobiids), or termites, for example,reticulitermes spp., heterotermes spp., coptotermes.

They have applications in the protection of stored products such asgrains, fruits, nuts, spices and tobacco, whether whole, milled orcompounded into products, from moth, beetle and mite attack. Alsoprotected are stored animal products such as skins, hair, wool andfeathers in natural or converted form (e.g., as carpets or textiles)from moth and beetle attack; also stored meat and fish from beetle, miteand fly attack.

The disclosure in U.S. provisional application No. 60/168,658 from whichthis application claims priority is incorporated herein by reference.

The invention is further illustrated by the following examples, withoutlimiting it thereto.

EXAMPLES AND PREPARATIONS Example 1 Preparation of1-(2,6-Dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfinyl-5-hydroxypyrazole

To a solution of 15 g (35.5 mmol) of1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-hydroxypyrazolein 125 ml of dichloromethane at room temperature was added a solution ofm-chloroperbenzoic acid (8.76 g, 70%, 35.5 mmol) in 375 ml ofdichloromethane. The resulting solution was stirred at room temperaturefor 17 hr. It was then concentrated and triturated with ethyl acetateand heptane(1:2). Upon filtration a solid was obtained. This solid wasdissolved in ethyl acetate and stirred with saturated sodium bicarbonatesolution. The layers were separated and the aqueous layer was extractedthree times with ethyl acetate. The combined organic layer was dried(magnesium sulfate) and concentrated. Upon chromatographic purificationvia silica gel column, a solid (5.7 g, 13.01 mol, 37%) was obtained asthe desired product, mp 185–187d.

Example 2 Preparation of1-(2,6-Dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfonyl-5-hydroxypyrazole

To the solution of 2 g (4.74 mmol) of1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-hydroxypyrazolein 1,2-dichloroethane was added 1.83 ml (9.52 mmol, 35% in acetic acid)of peracetic acid at room temperature. The resulting solution was heatedup to 60 C for 9 hr. It was then cooled and concentrated to give 2.05 gof residue. Upon chromatographic purification via silica gel columneluting with gradient solvent mixture (heptane/ethyl acetate), an oil(1.08 g, 2.38 mmol, 50.2% yield) was obtained as the desired productwith 98% HPLC purity; F-NMR, −60.999 ppm (AR—CF₃), −79.893 ppm (SO₂CF₃).H-NMR, 8.18 ppm (s, 2H).

Example 3 Preparation of1-(2,6-dichloro-4-trifluoromethylphenyl)-3-amido-4-trifluoromethylsulfenyl-5-hydroxypyrazole

To the mixture of1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-hydroxypyrazole(3.0 g, 7.13 mmol) and concentrated sulfuric acid (3 ml) was heated at100 C for 3 hr. The reaction mixture was cooled and poured intoice-water. A solid was collected via filtration and was washed withwater. It was then vacuum dried to obtain a solid (2.88 g, 6.56 mmol,92% yield) with 98% HPLC purity, m. p. 197–198 C.

Example 4 Preparation of1-(2,6-dichloro-4-trifluoromethylphenyl)-3-thioamido-4-trifluoromethylsulfenyl-5-hydroxypyrazole

The mixture of1-(2,6-dichloro-4-trifluoromethylphenyl)-3-amido-4-trifluoromethylsulfenyl-5-hydroxypyrazole(1 g, 2.28 mmol) and Lawesson's reagent (0.49 g, 1.21 mmol) in toluenewas heated up to reflux for 4 hr. The reaction mixture turned into asolution during this time. This solution was then cooled, concentrated,and purified via chromatographic purification to provide a solid (0.283g, 0.623 mmol, 27.3% yield) with 96% HPLC purity m. p. 150–151 decomp.

Example 5 Preparation of1-(2,6-Dichloro-4-trifluoromethylphenyl)-3-oximicamido-4-trifluoromethylsulfenyl-5-hydroxypyrazole

To the solution of1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-hydroxypyrazole(3.0 g, 7.11 mmol) in 15 ml of methanol at room temperature was addedhydroxyamine hydrochloride (0.59 g, 8.53 mmol) and triethylamine (0.94g, 9.24 mmol). The resulting mixture was stirred at room temperature fora total of 48 hr with additional hydroxyamine hydrochloride (1.18 g,17.06 mmol) and triethylamine (1.88 g, 18.5 mmol) added portionwise. Theresulting reaction mixture was concentrated and then dissolved in ethylacetate. The organic layer was washed with saturated ammonium chloride,water, dried (sodium sulfate), and concentrated to give a brown oilwhich solidified after standing, m. p. 184 C.

Example 6 Preparation of1-(2,6-Dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-trimethylacetoxypyrazole

To the solution of1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-hydroxypyrazole(7.00 g, 16.6 mmol) and pyridine (4.91 g, 62.1 mmol) in1,2-dichloroethane at room temperature was added trimethylacetylchloride (4.37 g, 36.2 mmol) dropwise. Ice bath was used to maintain thetemperature of the reaction. After 20 hr at room temperature, theorganic layer was washed five times with aqueous KHSO₄ till the aqueoussolution was at pH 1. The organic layer was then dried (MgSO₄) andconcentrated to give a solid residue. Upon chromatographic purificationvia silica gel column of the solid residue, after trituration withpentane, a off-white solid (2.403 g, 28.6% yield, 97.0% HPLC purity) wasprovided as the desired product, m. p. 82–83 C.

Example 7 Preparation of1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-chlorodifluoromethylsulfenyl-5-hydroxypyrazole

To the solution of1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-hydroxypyrazole (12.0g, 37.3 mmol.) and pyridine (3.25 g, 41.0 mmol) in dichloromethane at−50 to −60 C was added chlorodifluoromethanesulfenyl chloride (8.1 g,46.6 mmol). The resulting solution was gradually warmed up to roomtemperature. After 20 hr, the organic layer was washed five times withwater. It was then washed with brine and dried (Na₂SO₄) to provide anoil. Upon chromatographic purification of the oil, a total of 11.6 g(26.4 mmol., 71% yield) of the desired product with 97% HPLC purity wasisolated. F-NMR: −30.05 ppm (CClF₂), −63.80 ppm (ArCF₃).

BIOLOGICAL EXAMPLE

The compounds1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluromethylthio-5-hydroxypyrazole,1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfinyl-5-hydroxypyrazoleand1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfonyl-5-hydroxypyrazoleare formulated as 30 mg/mL formulations in a 1:1 volume/volume solutionof dimethyl sulfoxide and corn oil. Using this formulation, mixed breeddogs and cats are treated at a rate of 10 mg of the compound per kg(mg/kg)of body weight of the dog and 20 mg/kg of the cat treated. Theanimals are fasted for at least 8 hours prior to treatment, fed half ofthe daily ration immediately prior to treatment, then allowed access tothe remainder of the daily ration immediately following treatment.

All dogs are infested with cat fleas (Ctenocephalides felis) and withticks (Rhipicephalus sanguineus) 1 day prior to administration of thecompound. Cats are only infested with fleas. The initial flea and tickcounts are performed 1 day after the administration of the compounds. At7, 14, 21 and 28 days after treatment the dogs are re-infested withticks and 8, 15, 22 and 29 days after treatment the dogs and cats arere-infested with fleas. At 1, 9, 16, 23 and 30 days after treatment thecontrol of fleas and ticks in treated dogs and cats is determined versusa group of infested dogs and cats which receive a placebo consisting ofa 1:1 volume/volume solution of dimethyl sulfoxide and corn oil. Todetermine the efficacies of the compounds, the arthropods are combedfrom the animals and counted.

Satisfactory results are obtained for many of the above-mentionedcompounds in any of the three areas of evaluation without anysignificant side-effect for a period ranging from eight to thirty days:control of flea on dog, control of tick on dog, and control of flea oncat. They are:1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-trimethylacetoxypyrazole3-10,1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-ethoxypyrazole3-1,1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-chlorodifluoromethylsulfenyl-5-hydroxypyrazole1-9,1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-hydroxypyrazole1-1,1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfonyl-5-hydroxypyrazole1-5,1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfinyl-5-hydroxypyrazole1-3,1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluormethylsulfonyl-5-N,N-dimethylcarbamyloxypyrazole19-1.

1. A compound having the formula (II):

wherein: R₂₁ is cyano, C(═S)NH₂, C(═NOH)NH₂ or C(═NNH₂)NH₂; R₂₂ isS(O)_(m)R₂₃; R₂₃ is alkyl or haloalkyl; R₂₄ is OH, HC(O)O—, R₂₅C(O)O—,R₂₅OC(O)O—, R₂₅R₂₅N—C(O)—O— or R₂₅S(O)_(n)C(O)O—; R₂₅ is alkyl,haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl, haloalkoxyalkyl,adamantyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,haloalkylaminoalkyl, di(haloalkyl)aminoalkyl, aryl optionallysubstituted, hetaryl optionally substituted, arylalkyl optionallysubstituted, hetarylalkyl optionally substituted, C₂–C₆ alkenyl or C₂–C₆alkynyl; or two groups R₂₅ form together with the nitrogen to which theyare attached a 3 to 7 membered ring which optionally has one or moreadditional heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur; X is C—R₃₂; R₃₁ and R₃₂ are independently selectedfrom the group consisting of halogen, hydrogen, CN, C₁–C₃ alkyl and NO₂;R₃₃ is selected from the group consisting of halogen, haloalkyl,haloalkoxy, —S(O)_(r)CF₃ and SF₅; r is selected from the groupconsisting of 0, 1 and 2; and when R₂₁ is cyano, m is selected from thegroup consisting of 1 and 2, or when R₂₁ is other than cyano, m isselected from the group consisting of 0, 1 and 2; or a veterinarilyacceptable salt thereof; provided that when R₂₁ is cyano, then R₂₄ isnot R₂₅R₂₅—N—C(O)—O—.
 2. A compound according to claim 1, wherein: R₂₁is cyano; R₂₂ is S(O)_(m)R₂₃; R₂₃ is haloalkyl; R₂₄ is OH; X is C—R₃₂;R₃₁ and R₃₂ are independently selected from halogen; R₃₃ is selectedfrom the group consisting of halogen, haloalkyl, haloalkoxy,—S(O)_(r)CF₃, and —SF₅; r is selected from the group consisting of 0, 1,and 2; and m is selected from the group consisting of 1 and
 2. 3. Acompound according to claim 2, wherein R₂₃ is CF₃.
 4. The compoundaccording to claim 2, which is1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfinyl-5-hydroxypyrazole.5. The compound according to claim 2, which is1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfonyl-5-hydroxypyrazole.6. A composition comprising a parasiticidally effective, substantiallynon-emetic amount of a compound of formula (II) as defined in claim 1,or a veterinarily acceptable salt thereof, and a veterinarily acceptablecarrier therefor.
 7. A composition comprising a parasiticidallyeffective, substantially non-emetic amount of a compound as defined inclaim 2, and a veterinarily acceptable carrier therefor.
 8. Acomposition comprising a parasiticidally effective, substantiallynon-emetic amount of a compound as defined in claim 3, and aveterinarily acceptable carrier therefor.
 9. A composition comprising aparasiticidally effective, substantially non-emetic amount of a compoundas defined in claim 4, and a veterinarily acceptable carrier therefor.10. A composition comprising a parasiticidally effective substantiallynon-emetic amount of a compound as defined in claim 5, and aveterinarily acceptable carrier therefor.
 11. A compound having theformula (II):

wherein: R₂₁ is cyano, C(═S)NH₂, C(═NOH)NH₂ or C(═NNH₂)NH₂; R₂₂ isS(O)_(m)R₂₃; R₂₃ is alkyl or haloalkyl; R₂₄ is OH, HC(O)O—, R₂₅C(O)O—,R₂₅OC(O)O—, R₂₅R₂₅N—C(O)—O— or R₂₅S(O)_(n)C(O)O—; R₂₅ is alkyl,haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl, haloalkoxyalkyl,adamantyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,haloalkylaminoalkyl, di(haloalkyl)aminoalkyl, aryl optionallysubstituted, hetaryl optionally substituted, arylalkyl optionallysubstituted, hetarylalkyl optionally substituted, C₂–C₆ alkenyl or C₂–C₆alkynyl; or two groups R₂₅ form together with the nitrogen to which theyare attached a 3 to 7 membered ring which optionally has one or moreadditional heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur; X is C—R₃₂; R₃₁ and R₃₂ are independently selectedfrom the group consisting of halogen, hydrogen, CN, C₁–C₃ alkyl and NO₂;R₃₃ is selected from the group consisting of halogen, haloalkyl,haloalkoxy, —S(O)_(r)CF₃ and SF₅; m is selected from the groupconsisting of 1 and 2; and r is selected from the group consisting of 0,1 and 2; or a veterinarily acceptable salt thereof; provided that whenR₂₁ is cyano, then R₂₄ is not R₂₅R₂₅—N—C(O)—O—.
 12. A compound havingthe formula (II):

wherein: R₂₁ is cyano; R₂₂ is S(O)_(m)R₂₃; R₂₃ is alkyl or haloalkyl;R₂₄ is OH, HC(O)O—, R₂₅C(O)O—, R₂₅OC(O)O— or R₂₅S(O)_(n)C(O)O—; R₂₅ isalkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl,haloalkoxyalkyl, adamantyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, haloalkylaminoalkyl, di(haloalkyl)aminoalkyl, aryloptionally substituted, hetaryl optionally substituted, arylalkyloptionally substituted, hetarylalkyl optionally substituted, C₂–C₆alkenyl or C₂–C₆ alkynyl; or two groups R₂₅ form together with thenitrogen to which they are attached a 3 to 7 membered ring whichoptionally has one or more additional heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulfur; X is C—R₃₂; R₃₁ and R₃₂are independently selected from the group consisting of halogen,hydrogen, CN, C₁–C₃ alkyl and NO₂; R₃₃ is selected from the groupconsisting of halogen, haloalkyl, haloalkoxy, —S(O)_(r)CF₃ and SF₅; m isselected from the group consisting of 1 and 2; and r is selected fromthe group consisting of 0, 1 and 2; or a veterinarily acceptable saltthereof.
 13. A compound having the formula (II):

wherein: R₂₁ is C(═S)NH₂, C(═NOH)NH₂ or C(═NNH₂)NH₂; R₂₂ is S(O)_(m)R₂₃;R₂₃ is alkyl or haloalkyl; R₂₄ is OH, HC(O)O—, R₂₅C(O)O—, R₂₅OC(O)O— orR₂₅S(O)_(n)C(O)O— or R₂₅S(O)_(n)C(O)O—; R₂₅ is alkyl, haloalkyl,cycloalkyl, halocycloalkyl, alkoxyalkyl, haloalkoxyalkyl, adamantyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, haloalkylaminoalkyl,di(haloalkyl)aminoalkyl, aryl optionally substituted, hetaryl optionallysubstituted, arylalkyl optionally substituted, hetarylalkyl optionallysubstituted, C₂–C₆ alkenyl or C₂–C₆ alkynyl; or two groups R₂₅ formtogether with the nitrogen to which they are attached a 3 to 7 memberedring which optionally has one or more additional heteroatoms selectedfrom the group consisting of nitrogen, oxygen and sulfur; X is C—R₃₂;R₃₁ and R₃₂ are independently selected from the group consisting ofhalogen, hydrogen, CN, C₁–C₃ alkyl and NO₂; R₃₃ is selected from thegroup consisting of halogen, haloalkyl, haloalkoxy, —S(O)_(r)CF₃ andSF₅; m is selected from the group consisting of 0, 1 and 2; and r isselected from the group consisting of 0, 1 and 2; or a veterinarilyacceptable salt thereof.
 14. A composition comprising a parasiticidallyeffective, substantially non-emetic amount of a compound of formula (II)as defined in claim 11, or a veterinarily acceptable salt thereof, and aveterinarily acceptable carrier therefor.
 15. A composition comprising aparasiticidally effective, substantially non-emetic amount of a compoundas defined in claim 12, and a veterinarily acceptable carrier therefor.16. A composition comprising a parasiticidally effective, substantiallynon-emetic amount of a compound as defined in claim 13, and aveterinarily acceptable carrier therefor.
 17. A compound according toclaim 1, having the formula (II):

wherein: R₂₁ is cyano, C(═S)NH₂, C(═NOH)NH₂ or C(═NNH₂)NH₂; R₂₂ isS(O)_(m)R₂₃; R₂₃ is alkyl or haloalkyl; R₂₄ is OH, HC(O)O—, R₂₅C(O)O—,R₂₅OC(O)O—, R₂₅R₂₅N—C(O)—O— or R₂₅S(O)_(n)C(O)O—; R₂₅ is alkyl,haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl, haloalkoxyalkyl,adamantyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,haloalkylaminoalkyl, di(haloalkyl)aminoalkyl, aryl optionallysubstituted, arylalkyl optionally substituted, C₂–C₆ alkenyl or C₂–C₆alkynyl; X is C—R₃₂; R₃₁ and R₃₂ are independently selected from thegroup consisting of halogen, hydrogen, CN, C₁–C₃ alkyl and NO₂; R₃₃ isselected from the group consisting of halogen, haloalkyl, haloalkoxy,—S(O)_(r)CF₃ and SF₅; r is selected from the group consisting of 0, 1and 2; and when R₂₁ is cyano, m is selected from the group consisting of1 and 2, or when R₂₁ is other than cyano, m is selected from the groupconsisting of 0, 1 and 2; or a veterinarily acceptable salt thereof;provided that when R₂₁ is cyano, then R₂₄ is not R₂₅R₂₅—N—C(O)—O—.
 18. Acompound according to claim 11, having the formula (II):

wherein: R₂₁ is cyano, C(═S)NH₂, C(═NOH)NH₂ or C(═NNH₂)NH₂; R₂₂ isS(O)_(m)R₂₃; R₂₃ is alkyl or haloalkyl; R₂₄ is OH, HC(O)O—, R₂₅C(O)O—,R₂₅OC(O)O—, R₂₅R₂₅N—C(O)—O— or R₂₅S(O)_(n)C(O)O—; R₂₅ is alkyl,haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl, haloalkoxyalkyl,adamantyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,haloalkylaminoalkyl, di(haloalkyl)aminoalkyl, aryl optionallysubstituted, arylalkyl optionally substituted, C₂–C₆ alkenyl or C₂–C₆alkynyl; X is C—R₃₂; R₃₁ and R₃₂ are independently selected from thegroup consisting of halogen, hydrogen, CN, C₁–C₃ alkyl and NO₂; R₃₃ isselected from the group consisting of halogen, haloalkyl, haloalkoxy,—S(O)_(r)CF₃ and SF₅; m is selected from the group consisting of 1 and2; and r is selected from the group consisting of 0, 1 and 2; or aveterinarily acceptable salt thereof; provided that when R₂₁ is cyano,then R₂₄ is not R₂₅R₂₅—N—C(O)—O—.
 19. A compound according to claim 12,having the formula (II):

wherein: R₂₁ is cyano; R₂₂ is S(O)_(m)R₂₃; R₂₃ is alkyl or haloalkyl;R₂₄ is OH, HC(O)O—, R₂₅C(O)O—, R₂₅OC(O)O— or R₂₅S(O)_(n)C(O)O—; R₂₅ isalkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl,haloalkoxyalkyl, adamantyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, haloalkylaminoalkyl, di(haloalkyl)aminoalkyl, aryloptionally substituted, arylalkyl optionally substituted, C₂–C₆ alkenylor C₂–C₆ alkynyl; X is C—R₃₂; R₃₁ and R₃₂ are independently selectedfrom the group consisting of halogen, hydrogen, CN, C₁–C₃ alkyl and NO₂;R₃₃ is selected from the group consisting of halogen, haloalkyl,haloalkoxy, —S(O)_(r)CF₃ and SF₅; m is selected from the groupconsisting of 1 and 2; and r is selected from the group consisting of 0,1 and 2; or a veterinarily acceptable salt thereof.
 20. A compoundaccording to claim 13, having the formula (II):

wherein: R₂₁ is C(═S)NH₂, C(═NOH)NH₂ or C(═NNH₂)NH₂; R₂₂ is S(O)_(m)R₂₃;R₂₃ is alkyl or haloalkyl; R₂₄ is OH, HC(O)O—, R₂₅C(O)O—, R₂₅OC(O)O—,R₂₅R₂₅N—C(O)—O— or R₂₅S(O)_(n)C(O)O—; R₂₅ is alkyl, haloalkyl,cycloalkyl, halocycloalkyl, alkoxyalkyl, haloalkoxyalkyl, adamantyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, haloalkylaminoalkyl,di(haloalkyl)aminoalkyl, aryl optionally substituted, arylalkyloptionally substituted, C₂–C₆ alkenyl or C₂–C₆ alkynyl; X is C—R₃₂; R₃₁and R₃₂ are independently selected from the group consisting of halogen,hydrogen, CN, C₁–C₃ alkyl and NO₂; R₃₃ is selected from the groupconsisting of halogen, haloalkyl, haloalkoxy, —S(O)_(r)CF₃ and SF₅; m isselected from the group consisting of 0, 1 and 2; and r is selected fromthe group consisting of 0, 1 and 2; or a veterinarily acceptable saltthereof.
 21. A compound according to claim 1, having the formula (II):

wherein: R₂₁ is cyano, C(═S)NH₂, C(═NOH)NH₂ or C(═NNH₂)NH₂; R₂₂ isS(O)_(m)R₂₃; R₂₃ is alkyl or haloalkyl; R₂₄ is OH; R₂₅ is alkyl,haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl, haloalkoxyalkyl,adamantyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,haloalkylaminoalkyl, di(haloalkyl)aminoalkyl, aryl optionallysubstituted, arylalkyl optionally substituted, C₂–C₆ alkenyl or C₂–C₆alkynyl; X is C—R₃₂; R₃₁ and R₃₂ are independently selected from thegroup consisting of halogen, hydrogen, CN, C₁–C₃ alkyl and NO₂; R₃₃ isselected from the group consisting of halogen, haloalkyl, haloalkoxy,—S(O)_(r)CF₃ and SF₅; r is selected from the group consisting of 0, 1and 2; and when R₂₁ is cyano, m is selected from the group consisting of1 and 2, or when R₂₁ is other than cyano, m is selected from the groupconsisting of 0, 1 and 2; or a veterinarily acceptable salt thereof. 22.A compound according to claim 11, having the formula (II):

wherein: R₂₁ is cyano, C(═S)NH₂, C(═NOH)NH₂ or C(═NNH₂)NH₂; R₂₂ isS(O)_(m)R₂₃; R₂₃ is alkyl or haloalkyl; R₂₄ is OH; R₂₅ is alkyl,haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl, haloalkoxyalkyl,adamantyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,haloalkylaminoalkyl, di(haloalkyl)aminoalkyl, aryl optionallysubstituted, arylalkyl optionally substituted, C₂–C₆ alkenyl or C₂–C₆alkynyl; X is C—R₃₂; R₃₁ and R₃₂ are independently selected from thegroup consisting of halogen, hydrogen, CN, C₁–C₃ alkyl and NO₂; R₃₃ isselected from the group consisting of halogen, haloalkyl, haloalkoxy,—S(O)_(r)CF₃ and SF₅; m is selected from the group consisting of 1 and2; and r is selected from the group consisting of 0, 1 and 2; or aveterinarily acceptable salt thereof.
 23. A compound according to claim12, having the formula (II):

wherein: R₂₁ is cyano; R₂₂ is S(O)_(m)R₂₃; R₂₃ is alkyl or haloalkyl;R₂₄ is OH; R₂₅ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl,alkoxyalkyl, haloalkoxyalkyl, adamantyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, haloalkylaminoalkyl, di(haloalkyl)aminoalkyl, aryloptionally substituted, arylalkyl optionally substituted, C₂–C₆ alkenylor C₂–C₆ alkynyl; X is C—R₃₂; R₃₁ and R₃₂ are independently selectedfrom the group consisting of halogen, hydrogen, CN, C₁–C₃ alkyl and NO₂;R₃₃ is selected from the group consisting of halogen, haloalkyl,haloalkoxy, —S(O)_(r)CF₃ and SF₅; m is selected from the groupconsisting of 1 and 2; and r is selected from the group consisting of 0,1 and 2; or a veterinarily acceptable salt thereof.
 24. A compoundaccording to claim 13, having the formula (II):

wherein: R₂₁ is C(═S)NH₂, C(═NOH)NH₂ or C(═NNH₂)NH₂; R₂₂ is S(O)_(m)R₂₃;R₂₃ is alkyl or haloalkyl; R₂₄ is OH; R₂₅ is alkyl, haloalkyl,cycloalkyl, halocycloalkyl, alkoxyalkyl, haloalkoxyalkyl, adamantyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, haloalkylaminoalkyl,di(haloalkyl)aminoalkyl, aryl optionally substituted, arylalkyloptionally substituted, C₂–C₆ alkenyl or C₂–C₆ alkynyl; X is C—R₃₂; R₃₁and R₃₂ are independently selected from the group consisting of halogen,hydrogen, CN, C₁–C₃ alkyl and NO₂; R₃₃ is selected from the groupconsisting of halogen, haloalkyl, haloalkoxy, —S(O)_(r)CF₃ and SF₅; m isselected from the group consisting of 0, 1 and 2; and r is selected fromthe group consisting of 0, 1 and 2; or a veterinarily acceptable saltthereof.
 25. A composition comprising a parasiticidally effective,substantially non-emetic amount of a compound of formula (II) as definedin claim 17, or a veterinarily acceptable salt thereof, and aveterinarily acceptable carrier therefor.
 26. A composition comprising aparasiticidally effective, substantially non-emetic amount of a compoundas defined in claim 18, and a veterinarily acceptable carrier therefor.27. A composition comprising a parasiticidally effective, substantiallynon-emetic amount of a compound as defined in claim 19, and aveterinarily acceptable carrier therefor.
 28. A composition comprising aparasiticidally effective, substantially non-emetic amount of a compoundas defined in claim 20, and a veterinarily acceptable carrier therefor.29. A composition comprising a parasiticidally effective, substantiallynon-emetic amount of a compound of formula (II) as defined in claim 21,or a veterinarily acceptable salt thereof, and a veterinarily acceptablecarrier therefor.
 30. A composition comprising a parasiticidallyeffective, substantially non-emetic amount of a compound as defined inclaim 22, and a veterinarily acceptable carrier therefor.
 31. Acomposition comprising a parasiticidally effective, substantiallynon-emetic amount of a compound of formula (II) as defined in claim 23,or a veterinarily acceptable salt thereof, and a veterinarily acceptablecarrier therefor.
 32. A composition comprising a parasiticidallyeffective, substantially non-emetic amount of a compound as defined inclaim 24, and a veterinarily acceptable carrier therefor.